DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-2, 4, 12, 28, 41, 45, 48, 54, 58, 81, and 83) in the reply filed on 8/17/2026 is acknowledged.
Claims 1-2, 4, 12, 28, 41, 45, 48, 54, 58, 60-61, 65, 71, 75, 79-81, 83, and 227 are pending.
Claims 60-61, 65, 71, 75, 79-80, and 227 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/17/2026.
Claims 1-2, 4, 12, 28, 41, 45, 48, 54, 58, 81, and 83 are being examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (e.g., paragraph [0035]). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of the terms “HiSeq” and “NovaSeq” (paragraphs [0132 and 0159]), which are trade names or marks used in commerce, have been noted in this application. These terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 45, 48, 81, and 83 are objected to because of the following informalities:
Claim 1 reads “out of a total number of sequence reads from the plurality” and should read “out of a total number of sequence reads from the plurality of sequence reads” to maintain consistent claim terminology.
Claims 45 and 48 read “prior to providing the plurality of sequence reads” and should read “prior to [[providing]]obtaining the plurality of sequence reads” to maintain consistent claim terminology. Claim 1, from which both claims depend, recites a step “to obtain a plurality of sequence reads”. This makes it clear that the plurality of sequence reads are the same sequence reads as those obtained in claim 1.
Claim 81 reads “out of a total number of sequence reads from the plurality” and should read “out of a total number of sequence reads from the plurality of sequence reads” to maintain consistent claim terminology.
Claim 83 reads “at least one sequence read from the plurality” and should read “at least one sequence read from the plurality of sequence reads” to maintain consistent claim terminology.
Appropriate correction is required.
Claim Rejections - 35 USC § 112b - Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4, 12, 28, 41, 45, 48, 54, and 58 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “wherein at least the plurality of amplified nucleic acid fragments has undergone cytosine conversion”. It is unclear what is meant by “at least” in this context. Does this imply that only a subset of the plurality of nucleic acid fragments are amplified? It is unclear if this is the case given that the next line defines that the plurality of nucleic acid fragments correspond to a genomic locus comprising a cluster of two or more CpG dinucleotides, which implies that all of the plurality of nucleic acid fragments are of interest, would be amplified, and would be converted to cytosine. Or is this implying only the cytosine converted nucleic acids in the plurality are amplified (implying a methylation-specific amplification)? For the purposes of examination, it is being interpreted that the plurality of nucleic acids undergo cytosine conversion, and then are amplified, with no limitations as to whether said amplification is methylation-specific or not. Clarification is required.
Claims 2, 4, 12, 28, 41, 45, 48, 54, and 58 depend from claim 1, inherit this deficiency, and are rejected on the same basis.
Claim 2 recites the limitation “the CCF is at or above a threshold or reference value” and “the CCF is below a threshold or reference value”. It is unclear what the difference between a threshold and a reference value is. The recitation of both terms in the alternative indicates that there is some difference between how the values are applied to the CCF. However, in the specification there are no differing definitions and the two always appear together. To clear up ambiguity in the claim, one or the other should be chosen.
Claim 2 recites that cancer nucleic acids can be detected based on the comparison of the CCF to a threshold or reference value (at or higher indicates cancer nucleic acids, below indicates no cancer nucleic acids). However, the population used for the threshold or reference value is not defined. The specification indicates that a reference sample is any sample used for comparison (paragraph [0069]) and that the comparison values can be obtained from wild-type/non-tumor OR cancer or tumor cells (paragraph [0106]). The use of a healthy vs. a tumor reference value would significantly change the outcome of the claimed methodology and as such the reference population needs to be defined in the claim. For the purposes of examination, the threshold or reference value is being interpreted as indicative of a healthy control. However, clarification is required.
Claim 2 recites an additional method step of detecting the presence or absence of cancer nucleic acids “based at least in part on the CCF” comparison. It is unclear what other factors are being used to determine the presence or absence of cancer nucleic acids, given that only methylation levels/CCF is being determined in the method of claims 1 and 2. Clarification is required.
Claim 48 recites the limitation "the plurality of nucleic acids" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Claim 54 depends from claim 48, inherits this deficiency, and is rejected on the same basis.
Claim 54 recites “wherein the sample comprises tumor cell-free DNA (cfDNA), circulating cell-free DNA (ccfDNA), or circulating tumor DNA (ctDNA). It is unclear how tumor cell-free DNA and circulating tumor DNA are different, especially given that the specification states that “ctDNA is cfDNA with a genetic or epigenetic alteration (e.g., a somatic alteration or a methylation signature) that can discriminate it originating from a tumor cell versus a non-tumor cell” (paragraph [0144]). Stating that the cfDNA is tumor cfDNA necessarily makes it ctDNA according to the specification, however further clarification is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4, 12, 28, 41, 45, 48, 54, 58, 81, and 83 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (e.g.: a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim(s) is/are directed to a judicial exception encompassing abstract ideas (mental process and mathematical concepts) and natural phenomena. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception as set forth below. The judicial exception is not integrated into a practical application of the judicial exception.
The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Diamond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S._, (2010) (slip op., at 5). “Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U. S. 63, 67 (1972).
Additionally, the unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, No. 08-964, 2010 WL 2555192 (June 28, 2010) and in Alice Corp. v. CLS Bank Inti, 134 S. Ct. 2347, 2354 (2014).
The following inquiries are used to determine whether a claim is drawn to patent- eligible subject matter:
Step 1. Is the claim to a process, machine, manufacture, or composition of matter? Yes - the claims are directed to methods.
Step 2A, prong 1. Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? Yes -- Where the claims are directed to a “determining, by a processor, a consensus methylation pattern” and “generating, by a processor, a cluster consensus fraction” (claims 1 and 81) the claims are directed to a mathematical concept. Where the claims are directed to “detecting a methylation level based on the CCF”, “generating a genomic profile based on the detected methylation level”, and “detecting” the presence or absence of cancer nucleic acids based on the comparison of CCF to a threshold or reference value (claims 1, 2, and 81), the claims are directed to an abstract idea (a mental process); it is the mental identification of a phenotype, or the correlation of data and information.
Furthermore, the claims are directed to an asserted correlation between CCF and presence of cancer nucleic acids; such a correlation is a natural phenomenon which is an epigenome: phenotype relationship.
Step 2A, prong 2. Does the claim recite additional elements that integrate the judicial exception into a practical application? No - The judicial exception(s) to which the claims are directed are not integrated into a practical application because there are no required particular practical steps recited with specificity related to the generation of the genomic profile or identification of the presence or absence of cancer nucleic acids, such as applying a particular cancer treatment to the subject.
Step 2B. Does the claim recite additional elements that amount to significantly more than the judicial exception? No - The claims recite only routine steps related to obtaining a plurality of nucleic acids from a sample from a subject and performing methylation sequencing on cytosine converted DNA samples.
It is noted that the specification indicates that the practical steps of data collection in the claims were routinely practiced in the prior art. For example, the specification provides that methods for cytosine conversion are known in the art (paragraph [0121]), methods for WGMS and NGS are known in the art (paragraphs [0130 and 0132]), fragmentation techniques of nucleic acids prior to NGS or WGMS are used in the art (paragraph [0133]), PCR techniques are known in the art (for amplification, paragraph [0135]), obtaining sequencing reads from a sequencer is known in the art (paragraph [0162]). Additionally, methods of obtaining nucleic acid fragments from a sample from a subject, amplifying these fragments, and sequencing these fragments is taught in the art, as exemplified in Lambrechts et al.
So even where a practical step of the claim may require obtaining methylation data through conventional methods that have been practiced in the art, in University of Utah Res. Foundation v. Ambry Genetics Corp. (Fed Cir, 2014), the Court addressed claims that recite known methodological steps for collecting data (specifically genetic information) to be used in the application of a judicial exception, and held that:
Having determined that the comparison steps of claims 7 and 8 are abstract ideas, we move to the second step of Alice and ask whether the particular mechanism for the comparisons added by claims 7 or 8 renders the claims patent-eligible. For this step, Alice dictates that we ask whether the remaining elements, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to “transform the nature of the claim’ into a patent-eligible application.” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297). There must be a further inventive concept to take the claim into the realm of patent-eligibility. Id. at 2355. The second paragraph of claim 7 describes the way in which the sequences are compared: they are compared by 1) hybridizing a BRCA gene probe and 2) detecting the presence of a hybridization product. Similarly, claim 8 requires 1) amplification of the BRCA1 gene and 2) sequencing of the amplified nucleic acids. The non-patent-ineligible elements of claims 7 and 8 do not add “enough” to make the claims as a whole patent- eligible.
Additionally, In University of Utah Research v. Ambry Genetics the courts stated, "Recently in Alice the Supreme Court reiterated its two-step test to determine patent eligibility for any claims that allegedly encompass abstract ideas. First, "we determine whether the claims at issue are directed to [a] patent-ineligible concept. If so, we then ask, ‘what else is there in the claims before us?" Id. at 2355 (quoting Mayo, 132 S. Ct. at 1296-97) (citations and punctuation omitted). That is, we next ask whether the remaining elements, either in isolation or combination with the other non-patent- ineligible elements, are sufficient to " ‘transform the nature of the claim’ into a patent- eligible application." Id. at 2355 (quoting Mayo, 132 S. Ct. at 1297). Put another way, there must be a further "inventive concept" to take the claim into the realm of patent eligibility."
For these reasons the claims are rejected under 35 USC 101 as directed to subject matter that is not significantly more than a judicial exception.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 4, 12, 28, 41, 45, 48, 54, 81, and 83 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Lambrechts (Lambrechts et al., WO 2021/130356 A1; cited on IDS of 6/27/2024).
Claims 1, 81, and 83: Lambrechts teaches a method of detecting a methylation level of a cluster of two or more CpG dinucleotides in a sample from a subject (pg 3, ln 14-18). Lambrechts teaches obtaining crfDNA from a biological sample from a subject (which reads on obtaining a plurality of nucleic acid fragments from the sample; pg 6, ln 20-21). Lambrechts teaches amplifying the plurality of nucleic acid fragments (pg 20, ln 24-25). Lambrechts teaches that methylation analysis is by means of sequencing, wherein the plurality of amplified nucleic acid fragments has undergone cytosine conversion (pg 20, ln 5-25). Lambrechts teaches that the analysis of methylation level performed on a cluster of two or more CpG dinucleotides (“defined CpGs clusters”, pg 12, ln 32, pg 13, ln 20-30). Lambrechts demonstrates an example of an analyzed CpG cluster on page 14, which contains 19 CpG sites within a defined sequence region (also seen in Table 4, SEQ ID NO: 1; reads on a cluster of two or more CpG dinucleotides). Lambrechts teaches determining a consensus methylation pattern for the cluster which represents each CpG dinucleotide in the cluster for which methylation was detected based on the cytosine conversion in at least one sequence read (pg 53-54). Essentially, Lambrechts teaches defining a consensus pattern for each CpG dinucleotide in a defined cluster which corresponds most closely with ovarian cancer as compared to a normal control and comparing the frequency of this consensus pattern at the particular cluster in sequencing reads out of the total number of sequencing reads (thus defining a cluster consensus fraction; pg 53, ln 29-35-pg 54, ln 1-15 and pg 55, ln 24-26). Lambrechts teaches that this defines the methylation score (the methylation level) and thus reads on a genomic profile for the subject based on the detected methylation level (pg 53, ln 14-20). Lambrechts teaches that each step of this methodology involving determining, generating, or detecting can be performed by a computer or computer system which includes a processor (pg 14; pg 25, ln 20-30; pg 26, ln 1-10). Lambrechts teaches that high throughput sequencing performed for methylation sequencing was done on an Illumina HiSeq4000, thus teaching the performance of sequencing by a sequencer (pg 47, ln 16).
Claim 2: Lambrechts teaches detecting the presence of cancer nucleic acid fragments based on the cluster consensus fraction being at or above a threshold or reference value (Figure 8; pg 54, ln 6-15; pg 55, ln 24-26; pg 73, ln 5-11).
Claim 4: Lambrechts teaches performing the above methodology for more than one cluster (pg 8, ln 1-5; pg 75, ln 15-20).
Claim 12: Lambrechts teaches that at least one CpG dinucleotide in the cluster is methylated in the consensus methylation pattern (“hypermethylated or fully methylated CpG cluster” is more indicative of the test sample being cancerous, pg 55, ln 20-25).
Claim 28: Lambrechts teaches that the plurality of sequence reads is obtained from next-generation sequencing (pg 21, ln 9; pg 47, ln 4-20).
Claim 41: Lambrechts teaches that the nucleic acid fragments have undergone cytosine conversion by bisulfite treatment (pg 47, ln 4-20).
Claim 45: Lambrechts teaches selectively enriching the plurality of nucleic acid fragments corresponding to genomic loci that comprise a cluster of two or more CpG dinucleotides to produce an enriched sample (pg 47, ln 30-35; pg 54, ln 30-35, Table 4 - Probe).
Claim 48: Lambrechts teaches that the cfDNA is isolated (pg 6, ln 23; pg 10, ln 14; pg 19, ln 20-25).
Claim 54: Lambrechts teaches that the sample comprises tumor cfDNA or ctDNA (pg 47, ln 5-10).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over Lambrechts (Lambrechts et al., WO 2021/130356 A1; cited on IDS of 6/27/2024) in view of Urich (Urich et al., Nature Protocols 2015).
The teachings of Lambrechts, as they apply to claim 1, from which claim 58 depends, are detailed above. Relevant to the instantly rejected claim, Lambrechts teaches determining the methylation level of cfDNA from a biological sample from a subject.
Lambrechts teaches that their methodology can also be applied to tissue samples (pg 47, ln 4), but does not specify that the plurality of nucleic acid molecules in the tissue are subjected to fragmentation to create a plurality of nucleic acid fragments. However, fragmentation of gDNA from tissue samples for methylation sequencing is known in the art, as taught by Urich.
Urich teaches a method of methylation sequencing in which purified genomic DNA is first fragmented before being subjected to bisulfite conversion and sequencing (Overview of MethylC-seq).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Lambrechts to include fragmentation of the genomic DNA from tissue samples, as taught by Urich. One would be motivated to do so given that Urich teaches that methylation sequencing involving fragmentation of gDNA can be applied to gDNA derived from animal tissues and used in processes such as bisulfite conversion for sequencing and that the protocol involving gDNA digestion is designed around “standard protocols designed to construct DNA sequencing libraries” (Overview of MethylC-Seq and Anticipated results). One would have a reasonable expectation of success given that Urich indicates that this methodology has been successfully applied for methylation sequencing on animal tissues (Abstract).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/ Examiner, Art Unit 1683
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683
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